MAYO CLINIC JACKSONVILLE - Subcontract PROJECT SUMMARY The amyloid plaques composed of amyloid-? (A?) and neurofibrillary tangles containing hyperphosphorylated tau are pathological hallmarks of Alzheimer?s disease (AD). Recent studies have shown that these pathological lesions progressively spread from one brain region to another likely through a trans-synaptic mechanism. The major goal of Project 3 is to dissect the molecular and cellular pathways that either promote or inhibit A?/tau spreading with a specific focus on neuronal receptors LRP1 and heparan sulfate proteoglycan (HSPG). As the ?4 allele of the apolipoprotein E gene (APOE4) is the strongest genetic risk factor for late-onset AD, we will also evaluate the apoE isoform-specific effects on A?/tau spreading and whether such effects depend on the presence of neuronal LRP1/HSPG. During the previous funding cycle, Project 3 has defined the roles of apoE isoforms and apoE receptor LRP1 and HSPG in brain A? metabolism, establishing the opposing roles of LRP1 (beneficial) and HSPG (harmful) in brain A? metabolism, as well as the modulatory effects of apoE isoforms. HSPG has been suggested to promote pathological spreading of tau. Importantly, our preliminary studies in collaboration with Project 1 (Holtzman, PI) have also demonstrated a role of LRP1 in cellular uptake of tau monomer and aggregates. Further, we have detected an apoE isoform-dependent effects on tau-mediated behavioral deficits in mice, thus linking A?, tau, apoE, LRP1 and HSPG in related pathogenic pathways. Thus, we hypothesize that LRP1 inhibits and HSPG promotes the speed and extent of pathological spreading of A? and tau aggregates, and that apoE further modulates these events in an isoform-specific manner. We propose three specific aims to address our hypothesis. In Aim 1, we will examine how neuronal LRP1 and HSPG modulate pathological spreading of A? and tau aggregates in vivo using conditional mouse models. We will also address how the presence of amyloid pathology impacts tau pathology and spreading in an LRP1- or HSPG-dependent manner, In Aim 2, we will analyze how apoE isoforms modulate pathological spreading of tau aggregates and whether any apoE effects depend on the presence of LRP1, HSPG, or amyloid pathology. Conditional mouse models as well as viral mediated expression of apoE isoforms will be employed in these studies. In Aim 3, we will dissect the mechanisms by which LRP1, HSPG and apoE isoforms regulate cellular trafficking, degradation or accumulation of various aggregated forms of A? and tau. Mouse primary neurons, induced pluripotent stem cell (iPSC)-derived human neurons, as well as microfluidic platform will be used for these studies. Interactions with other PPG projects will include evaluating the effects of neuronal activities and sleep/wake cycle on LRP1/HSPG/apoE-dependent A?/tau spreading. This project will use Viral Vector Core for the production of AAV and lentiviral vectors for in vivo and in vitro studies. Together, these studies should generate critical insights into the molecular mechanism underlying A?/tau spreading and inform strategies for mechanism-based therapy to combat AD and other neurodegenerative diseases with tauopathies.